Myelofibrosis

Myelofibrosis is a serious bone marrow disorder that disrupts your body's normal production of blood cells. The result is extensive scarring in your bone marrow, leading to severe anemia, weakness, fatigue, and often, an enlarged spleen and liver.
Myelofibrosis — also called agnogenic myeloid metaplasia or idiopathic myelofibrosis — can occur at any age, although it mainly develops after age 50.
Many people with myelofibrosis get progressively worse, and some eventually develop a serious form of leukemia. Yet it's also possible to have myelofibrosis and live symptom-free for years. Treatment for myelofibrosis, which focuses on relieving symptoms, can involve a variety of options.

Symptoms:

Myelofibrosis usually develops slowly. In its very early stages, many people don't experience signs or symptoms. But as disruption of normal blood cell production increases, signs and symptoms may include:
• Feeling tired, weak or short of breath, usually because of anemia
• Pain or fullness below your ribs on the left side, due to enlarged spleen
• Enlarged liver
• Pale skin
• Easy bruising
• Easy bleeding
• Excessive sweating during sleep (night sweats)
• Fever
• Frequent infections
• Bone pain
When to see a doctor
Make an appointment to see your doctor if you:
• Feel run-down or tired
• Have a feeling of unusual fullness in your left abdomen
• Experience unexplained weight loss
• Sweat excessively during sleep
• Have other possible signs and symptoms of myelofibrosis
These signs and symptoms, although vague, should be checked out by your doctor.

Causes & Complication

Causes:

The process of producing blood cells in your body is called hematopoiesis. This process starts in your bone marrow with a certain type of cell called a hematopoietic stem cell. A stem cell is a primitive, undifferentiated cell that has the ability to replicate and then divide into multiple specialized cells — red blood cells, white blood cells and platelets.
These specialized blood cells have a limited life span. When they grow old, they die off naturally and are replaced by new cells, in a continuous, healthy cycle.
How myelofibrosis occurs
Myelofibrosis occurs when the genetic material in a single hematopoietic stem cell changes, or mutates. What causes this mutation is often unknown, but it's usually an acquired mutation that develops during your lifetime rather than one that's present at birth (congenital).
When the mutated cell replicates and divides, it passes along the mutation to the new cells. As more and more of these mutated cells are created, they begin to have serious effects on blood production. The end result is usually a lack of red blood cells — which causes the anemia characteristic of myelofibrosis — and an overabundance of white blood cells with varying levels of platelets.
Because of the overproduction of white blood cells, doctors refer to myelofibrosis as a myeloproliferative disease, a type of disease characterized by uncontrolled production of one or more types of blood cells. Scarring (fibrosis) within the bone marrow is thought to be a secondary reaction to the activity of the mutated cells. Your spleen and sometimes your liver may become enlarged when they trap excess white blood cells circulating through your body.
Although the cause of myelofibrosis often isn't known, certain factors are known to increase your risk:
• Age. Myelofibrosis can affect anyone, but it's most often diagnosed in people between the ages of 50 and 80. The condition is usually rare in children with the exception of a form that tends to run in families.
• Genetic mutations. Some people with myelofibrosis have a mutation in the JAK2 gene or in the MPL gene.
• Exposure to toxins. In a few cases, myelofibrosis has been linked to exposure to carcinogenic chemicals such as thorium dioxide, toluene and benzene and to ionizing radiation.
• Exposure to contrast material. Some people who received an X-ray contrast material called Thorotrast in the 1930s and 1940s have since developed myelofibrosis.

Complications:

Complications that may result from myelofibrosis include:
• Increased pressure on blood flowing into your liver. Normally, blood flow from the spleen enters your liver through a large blood vessel called the portal vein. Increased blood flow from an enlarged spleen can lead to high blood pressure in the portal vein (portal hypertension). This in turn can force excess blood into smaller veins in your stomach and esophagus, potentially causing these veins to rupture and bleed. If problems develop, your doctor may recommend removal of your spleen.
• Pain in your upper left side or shoulder. This may result from episodes of inflammation or tissue death in your spleen. Pain relievers can usually help control symptoms.
• Other organ involvement. Formation of blood cells outside the bone marrow (extramedullary hematopoiesis) may create clumps (tumors) of developing blood cells in other areas of your body. These tumors may cause problems such as bleeding in your gastrointestinal system, coughing or spitting up of blood, compression of your spinal cord, or seizures. Extramedullary blood formation is usually treated with low-dose radiation.
• Infections. Myelofibrosis can cause the overproduction of white blood cells, which help fight infection. But in myelofibrosis, these blood cells often aren't fully formed or are mutated so that they become ineffective, actually decreasing your ability to fight off infections.
• Bleeding complications. As the disease progresses, platelet count tends to drop below normal (thrombocytopenia) and platelet function becomes impaired. An insufficient number of platelets can lead to easy bleeding — an issue that you and your doctor will want to discuss if you're contemplating any type of surgical procedure.
• Hardening and inflammation of bone tissue. Myelofibrosis can lead to hardening of your bone marrow as well as inflammation of the connective tissue that surrounds your bones, leading to severe bone and joint pain and tenderness.
• Gout. Myelofibrosis increases your body's production of uric acid, a byproduct of the breakdown of purines — a substance found naturally in your body and in many foods. Overproduction of uric acid can lead to needle-like deposits of the substance in your joints, causing joint pain and inflammation (gout). You may need medications to keep your levels of uric acid normal.
• Acute leukemia. Some people with myelofibrosis eventually develop acute myelogenous leukemia, a type of blood and bone marrow cancer that progresses rapidly.

Tests

Tests and Diagnosis:

In people who have no symptoms, a routine medical checkup revealing an enlarged spleen and abnormal blood test results may spark suspicions of a medical problem. If you come to your doctor because of troublesome symptoms, a physical exam and blood tests are likely the first steps your doctor will take.
To confirm a diagnosis of myelofibrosis, you may have imaging studies of your bones, spleen and liver, and examination of a sample of your bone marrow.
• Physical exam. Your doctor will perform a thorough physical exam. This includes a check of such vital signs as pulse and blood pressure, as well as checks of your lymph nodes, spleen and abdomen.
• Blood tests. In myelofibrosis, a complete blood count typically shows abnormally low levels of red blood cells, a sign of anemia common in people with myelofibrosis. White blood cell and platelet counts are usually abnormal, too. Often, white blood cell levels are higher than normal, although in some people they may be normal or even lower than normal. Platelet counts may be higher or lower than normal.
• Imaging tests. Imaging tests such as ultrasound, magnetic resonance imaging (MRI) and computerized tomography (CT) scans can help determine if your spleen and liver are enlarged. Your doctor may be able to detect enlargement of these organs just by feeling your abdomen, but imaging tests can help identify the degree of enlargement.
• Bone marrow examination. Bone marrow biopsy and aspiration are essential to confirming a diagnosis of myelofibrosis. Because this is a more invasive procedure, it's usually done last, to confirm other test results. In a bone marrow biopsy, a special needle is used to draw a sample of bone marrow from your hipbone. During the same procedure, an aspiration needle may be used to withdraw a sample of the liquid portion of your bone marrow. Studying genetic components (cytogenetic study) of bone marrow sample cells can reveal chromosomal abnormalities and may help to rule out other kinds of bone marrow disorders.

Medication & Prevention

Treatments and Drugs:

If you aren't experiencing symptoms and don't show signs of anemia, an enlarged spleen or other complications, treatment usually isn't necessary. Instead, your doctor is likely to monitor your health closely through regular checkups and exams, watching for any signs of disease progression. Some people remain symptom-free for years.
For people with serious symptoms or complications, treatment options typically include:
• Blood transfusions. If you have severe anemia, periodic blood transfusions can increase your red blood cell count and ease anemia symptoms, such as tiredness and weakness. Sometimes, medications can help improve anemia so that you don't need blood transfusions.
• Androgen therapy. Taking a synthetic version of the male hormone androgen combined with a corticosteroid medication, such as prednisone, can promote red blood cell production and may improve severe anemia in some people. People who respond to this treatment after a month of therapy may continue on with the androgen and slowly taper off the prednisone. Androgen therapy does have risks, including liver damage, masculinizing effects in women, and growth of prostate cancer cells.
• Chemotherapy. Hydroxyurea (Hydrea) is the most commonly used chemotherapy drug in treating myelofibrosis. Hydroxyurea can reduce the size of an enlarged spleen, decrease high platelet counts, improve night sweats and weight loss, and possibly reduce bone marrow fibrosis.
• Radiation therapy. Radiation may help a small number of people who have bone pain. It can also help reduce the size of the spleen, when surgical removal isn't an option.
• Thalidomide with steroids. Using thalidomide along with prednisone can help reduce spleen size, improve anemia and white blood cell and platelet counts, and improve other systemic symptoms, such as weakness, fatigue, night sweats and shortness of breath. This therapy can also reduce the need for blood transfusions, but it's still fairly experimental.
• Surgical removal of the spleen (splenectomy). If the size of your spleen becomes painful and begins to cause harmful complications, and if you don't respond to other forms of therapy, you may benefit from having your spleen surgically removed. Risks include infection, excessive bleeding, blood clot formation leading to stroke or pulmonary embolism, and a higher rate of conversion to acute leukemia. After the procedure, some people experience liver enlargement and an abnormal increase in platelet count.
• Stem cell transplantation. Allogeneic stem cell transplantation — stem cell transplantation from a suitable donor — is the only treatment that has the potential to cure myelofibrosis. But it also has a high risk of life-threatening side effects because it requires high doses of chemotherapy and radiation before transplantation to destroy the diseased cells. After the procedure, there's a risk that the new stem cells will react against your body's healthy tissues, causing potentially fatal damage (graft-versus-host disease). Other risks include organ or blood vessel damage, cataracts, and the development of a different cancer later on. Most people with myelofibrosis, because of age, stability of the disease or other health problems, don't qualify for this treatment.
Under investigation
Currently being studied is a reduced-intensity transplant, also called a nonmyeloablative transplant or mini-transplant. Reduced-intensity transplants use lower doses of pre-transplant chemotherapy and radiation, relying instead on the donor's immune system to destroy diseased cells. Although reduced-intensity transplantation has side effects, doctors hope that it will be safer but just